Depression is one of the most prevalent mental disorders in the United States and is associated with high levels of morbidity and mortality. It is estimated that costs associated with depression (from absenteeism, lost productivity, lost earnings, treatment and rehabilitation) exceed $40 billion in the United States alone. Our work is focused on the investigation of the mechanism of depression and antidepressant drug action. We developed a new animal model of depression, reduction of submissive behavior (RSBM) that differs from existing behavioral tests by not subjecting animals to pain or artificially stressful conditions. Instead, pairs of rats compete during a daily 5-minute trial period for a limited amount of food. Half of the rats tested under this condition develop a dominant/submissive relationship that is a characteristic feature of normal animal social behavior. The submissive behavior observed can be objectively measured as the amount of time spent on the feeder relative to that by the paired dominant animal. We have shown that this submissive behavior has qualities of human depression and can be greatly reduced or eliminated by treatment with a wide variety of antidepressant drugs. We want to adopt the RSBM to mice for testing mouse mutants for candidate gene related to depression. The extension of the dominance-submissive model to mice is of particular importance because of the development of many genetically distinct mouse strains and the availability of mice with specific genetic modifications (i.e. knockout strains). The studies in this proposal are designed to test the hypothesis that mice, like rats, will form dominant-submissive behavior and to demonstrate the activity of antidepressant drugs in mice using the model as described above. We will also determine whether selected mouse strains are more prone to submissiveness than others. Furthermore we will study whether specific knockout mice showing depressive-like behaviors in other models of depression will be submissive as compared with the wild type animals. Human depression shows an inheritance pattern consistent with a genetic component. The identification of genetic elements in mice associated with depression-like behavior can be tested for homology in human patients that could ultimately lead to an understanding of genetic defects underlying depression in humans.